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Role of 20-HETE in Pediatric Traumatic Brain Injury

20-HETE 在小儿创伤性脑损伤中的作用

基本信息

批准号：
9883849
负责人：
COURTNEY L ROBERTSON
金额：
$ 35.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883849
关键词：
Adenosine Diphosphate Ribose Adult Adverse effects Adverse event Alkane 1-monooxygenase Animal Model Anti-Inflammatory Agents Arachidonic Acids Area Attention Attenuated Brain Brain hemorrhage CASP8 gene Caspase Cell Death Cells Cerebral Ischemia Child Childhood Craniocerebral Trauma Cytochrome P450 Cytochrome a Cytochromes Data Development Enzymes Event Family Female Goals Heart Arrest Hippocampus (Brain)Hour Hydroxyeicosatetraenoic Acids Infant Inflammation Inflammatory Injury Investigation Ischemic Stroke Lead Learning Lesion Life Lipopolysaccharides Lymphocyte Membrane Lipids Microglia Mixed Function Oxygenases Modeling Morphology N-Methyl-D-Aspartate Receptors NADPH Oxidase Na(+)-K(+)-Exchanging ATPase Neurodegenerative Disorders Neurologic Neuronal Injury Neurons Neutrophil Infiltration Nuclear Nucleic Acids Outcome Oxidative Stress Pathway interactions Pediatric Brain Injury Pharmaceutical Preparations Phosphorylation Phosphotransferases Polymers Process Protein Isoforms Proteins Public Health RIPK1 gene RIPK3 gene Rattus Recovery Research Role Sensorimotor functions Sex Differences Signal Transduction Social Behavior Social Functioning Stress Stroke Supportive care Testing Thalamic structure Therapeutic Toddler Translations Traumatic Brain Injury United States Work apoptosis inducing factor appropriate dose base clinically relevant cognitive function controlled cortical impact cytokine disability excitotoxicity improved improved outcome infant brain injury inhibitor/antagonist innovation insight male member neonatal hypoxic-ischemic brain injury neuroinflammation neuron loss neuroprotection novel outcome forecast pediatric traumatic brain injury postnatal programs progressive neurodegeneration public health relevance response therapeutic target young adult

项目摘要

DESCRIPTION (provided by applicant): Millions of infants, children and young adults are living with disabilities resulting from traumatic brain injury (TBI) in childhood. Following the intial insult, a cascade of secondary events produces progressive neurodegeneration. The developing brain may be uniquely vulnerable to some of these secondary insults, due to maturational features. In the very young, the injury may interfere with the execution of the developmental program later in life, leading to learning, attention, and social behavior abnormalities. Currently, treatment is limited to supportive care. Here, we will investigate novel emerging pathways involving cell signaling by 20- HETE, a cytochrome P450 metabolite of arachidonic acid. We find that specific cytochrome P450s known to synthesize 20-HETE are expressed in neurons and microglia and that 20-HETE can induce phosphorylation of NMDA receptors and Na,K-ATPase. Based on our previous work showing that a 20-HETE inhibitor is neuroprotective in models of neonatal hypoxia-ischemia and adult ischemic and hemorrhagic stroke, we began to study its effect in the controlled cortical impact model in postnatal day 10 rats. Preliminary data show large reductions in lesion volume, improved long-term sensorimotor function, attenuated morphological changes in microglia, and a reduction of pro-inflammatory cytokines. The 20-HETE inhibitor also attenuated the response to lipopolysaccharide in microglia cultures. The goal of this project is to investigate the role of 20-HETE in males and females in a model of pediatric TBI. In Aim 1, we will determine the optimal duration of 20-HETE inhibitor administration and the maximum delay that provides efficacy so as to inform when 20-HETE signaling is exerting adverse effects after TBI. In Aim 2, we will determine the effects of 20-HETE inhibition after TBI on NADPH oxidase and the consequent downstream effects on key caspase-dependent and independent cell death pathways. In Aim 3, we will determine the effects of 20-HETE inhibition after TBI on microglia morphology and the cytokine profile. By targeting both cell death and inflammatory pathways with a single drug in the very immature brain, this work has great potential for improving outcome from TBI in infants and toddlers who often have the poorest prognosis in pediatric TBI. Moreover, emerging evidence with cerebral ischemia indicates sex differences in cell death mechanisms and inflammation in both immature and mature brain, yet sex differences have been understudied in pediatric TBI models. Thus, the proposed work also is innovative in that it will begin to reveal whether sex differences in response to neuroprotective therapies are operative after TBI in the immature brain. Finally, elucidation of new pathways of 20-HETE in neurons and microglia could have an important bearing beyond TBI for other neurodegenerative disorders involving excitotoxicity and neuroinflammation and, hence, may stimulate new areas of investigation.

描述（由申请人提供）：数以百万计的婴儿、儿童和年轻人因童年时期的创伤性脑损伤（TBI）而患有残疾。初次损伤后，一系列继发事件会导致进行性神经变性。由于成熟的特征，发育中的大脑可能特别容易受到这些继发性损伤的影响。对于年幼的孩子来说，这种伤害可能会干扰日后发育计划的执行，导致学习、注意力和社交行为异常。目前，治疗仅限于支持性护理。在这里，我们将研究涉及 20-HETE（花生四烯酸的细胞色素 P450 代谢物）细胞信号传导的新兴途径。我们发现已知合成 20-HETE 的特定细胞色素 P450 在神经元和小胶质细胞中表达，并且 20-HETE 可以诱导 NMDA 受体和 Na,K-ATP 酶的磷酸化。基于我们之前的研究表明20-HETE抑制剂在新生儿缺氧缺血和成人缺血性和出血性中风模型中具有神经保护作用，我们开始研究其在出生后第10天大鼠的受控皮质冲击模型中的作用。初步数据显示，病变体积大幅缩小，长期感觉运动功能得到改善，小胶质细胞形态变化减弱，促炎细胞因子减少。 20-HETE 抑制剂还减弱了小胶质细胞培养物中对脂多糖的反应。该项目的目标是在儿科 TBI 模型中研究 20-HETE 在男性和女性中的作用。在目标 1 中，我们将确定 20-HETE 抑制剂给药的最佳持续时间和提供功效的最大延迟时间，以便在 TBI 后告知 20-HETE 信号传导何时产生不利影响。在目标 2 中，我们将确定 TBI 后 20-HETE 抑制对 NADPH 氧化酶的影响，以及随后对关键的 caspase 依赖性和独立细胞死亡途径的下游影响。在目标 3 中，我们将确定 TBI 后 20-HETE 抑制对小胶质细胞形态和细胞因子谱的影响。通过在非常不成熟的大脑中使用单一药物靶向细胞死亡和炎症途径，这项工作对于改善婴儿和幼儿的 TBI 结局具有巨大的潜力，因为婴儿和幼儿的 TBI 预后往往最差。此外，新出现的脑缺血证据表明，未成熟和成熟大脑中的细胞死亡机制和炎症存在性别差异，但在儿童 TBI 模型中，性别差异尚未得到充分研究。因此，拟议的工作也具有创新性，因为它将开始揭示在未成熟大脑中发生 TBI 后，对神经保护疗法反应的性别差异是否有效。最后，阐明 20-HETE 在神经元和小胶质细胞中的新通路可能对 TBI 之外的涉及兴奋性毒性和神经炎症的其他神经退行性疾病产生重要影响，因此可能会刺激新的研究领域。